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WO1998000391A1 - Derives de cyclopropylglycine et agoniste du recepteur du l-glutamate du type a regulation metabolique - Google Patents

Derives de cyclopropylglycine et agoniste du recepteur du l-glutamate du type a regulation metabolique Download PDF

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Publication number
WO1998000391A1
WO1998000391A1 PCT/JP1996/003849 JP9603849W WO9800391A1 WO 1998000391 A1 WO1998000391 A1 WO 1998000391A1 JP 9603849 W JP9603849 W JP 9603849W WO 9800391 A1 WO9800391 A1 WO 9800391A1
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WIPO (PCT)
Prior art keywords
cyclopropylglycine
represent
group
difluoro
carboxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1996/003849
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English (en)
Japanese (ja)
Inventor
Haruhiko Shinozaki
Takeo Taguchi
Michiko Ishida
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Nippon Chemiphar Co Ltd
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Nippon Chemiphar Co Ltd
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Application filed by Nippon Chemiphar Co Ltd filed Critical Nippon Chemiphar Co Ltd
Priority to EP96943327A priority Critical patent/EP0913389A4/fr
Publication of WO1998000391A1 publication Critical patent/WO1998000391A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to a novel cyclopropylglycine derivative and a metabolically regulated L-glutamic acid receptor agonist containing the cyclopropylglycine derivative as an active ingredient.
  • glutamate receptors are largely classified into ion channel type (iGluR) and metabolic regulation type (mG1uR). And iG1uR is further classified into NMDA (N-methyl-D-aspartate) type and non-NMDA type.
  • iGluR ion channel type
  • mG1uR metabolic regulation type
  • NMDA N-methyl-D-aspartate
  • non-NMDA non-NMDA
  • NMD type A receptor the action of this receptor, activated by agonists, causes Ca 2+ to enter the cell and increase the intracellular Ca 2+ concentration, and as a result, It has been speculated that when Ca 2+ -dependent enzymes are activated and the subsequent cascading intracellular changes exceed a certain threshold, they shift to irreversible cell death. (The Japanese Pharmacological Journal, 104, 177-187 (1994))
  • mGluRs are currently divided into three groups (group I, ⁇ , ⁇ ) based on their sequence homology, intracellular signal transduction mechanism, and agonist selectivity.
  • group I As an mG 1 uR group I agonist, quisqualic acid has a strong activity, which promotes the production of inositol triphosphate (IP 3 ) and changes in intracellular Ca kinetics.
  • IP 3 inositol triphosphate
  • the agonists of the mGliR ⁇ ⁇ , ⁇ inhibit the production of intracellular cAMP induced by forskol ⁇ n. There is a difference in agonist selectivity between the questions of mG 1 uR groups ⁇ and ⁇ 1.
  • An agonist of mG 1 u R group DC is DCC — IV (2 S, 1 'R, 2 * R, 3 'R) — 2— (2,3-dicarboxycyclopropyl) glycine) and L— CCG— I ((2 S, 1 ′ S, 2 ′ S)-2-(2—carboxy Cyclobutyryl) and glycine) are known, and L-AP4 (L-2-amino-41-phosphonolanic acid) is known as an agonist of group m of mG1uR.
  • Japanese Unexamined Patent Publication No. 6-256323 Japanese Unexamined Patent Application Publication No. 6-24970, "Neuropsychopharmacology", Vol. 18, No. 6, pp. 419-425, 1996)
  • agonists belonging to the group II of mG 1 uR suppress the release of transmitters at synapses, thereby decreasing the efficiency of synaptic transmission.
  • Poor synaptic transmission in the central nervous system is considered to be a muscle relaxing force for the motor system.
  • animal experiments have confirmed that a significant increase in anesthesia was observed when used in combination with an anesthetic.
  • sedation, tranquilizer-like effects, and antiepileptic effects have been observed.
  • agonists belonging to the group III of mG1 uR have an action to protect neuronal cell death caused by excitatory amino acids in invitro and invivo, and thus have high expectations as a neuroprotective agent.
  • such a central inhibitory effect is an unprecedented new form of glutamate receptor agonist, and is indispensable for the study of centrally acting drugs in the future. high. (“Nichi Pharmaceutical Journal” No. 104, pp. 177-187 (1994)).
  • DCG-IV an agonist belonging to the group III of mG1uR, strongly activates mGluR, and thus has potential for neuronal protective action.
  • the DCG- IV in addition to activating mG 1 uR, also known force s activates NMDA receptors which is thought to have an association between neuronal death by excitatory amino acids Therefore, development of a new agonist of mG1uR having no NMDA component is awaited.
  • the present invention provides the following general formula (I):
  • R 'and R 2 each independently represent a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms
  • R 3 and FT each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • X 1 and X 2 each independently represent a halogen atom.
  • the present invention also provides a metabolic-regulated L-glutamic acid receptor agonist comprising, as an active ingredient, the cyclopropylglycine derivative represented by the above general formula (I).
  • the present invention also resides in a pharmaceutical composition comprising, as an active ingredient, the cyclopropylglycine derivative represented by the general formula (I).
  • the intermediate provided by the present invention has the following general formula (2):
  • R 2 represents a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms
  • R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • X ′ and X 2 are respectively Independently represents a halogen atom.
  • It is a lactam derivative represented by these.
  • R 1 and R 2 are each independently a hydroxyl group or an alkoxy group having 1 to 6 carbon atoms (eg, methoxy group, ethoxy group, n- propoxy group, isopropoxy group, n-butoxy group)
  • R 3 and FT each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (eg, a methyl group, an ethyl group, an n-bromo group, an isopropyl group, an n-butyl group).
  • X 1 and X 2 each independently represent a halogen atom (eg, fluorine, chlorine, bromine, iodine).
  • the pyruglycine derivative of the present invention may be in a free acid state or a salt state.
  • the cyclopropylglycine derivative of the present invention is represented by the general formula (I) wherein R 1 and R 2 and s each represent a hydroxyl group, R 3 and R 4 both represent a hydrogen atom, and X 1 and X 2 both represent a hydrogen atom. It is preferably a compound representing a fluorine atom (that is, 2- (2'-carboxy-3 ', 3'-difluoro) cyclobutylpyrglycine). This compound has a total of 8 optical isomers as follows.
  • the cyclopropylglycine derivative of the present invention can be prepared by using a known olefin compound (E-1 or Z-1: J. Or. Chem., 59 (1), 97-) as shown in the following reaction scheme-1. 103 (1994)) with sodium chlorodifluoroacetate to react with 2- (2'-benzyloxymethyl-3 ', 3'-difluoro) cyclobutyryl ethylene glycol 1,2-0-acetonide Optically active isomers were obtained (the reaction from E-1 is described in Tetrahedron: Asymmetry, 5 (8), 1423-1426 (1994)), and then these were reacted as starting materials. It can be obtained by using the method shown in Scheme-2 (Examples of production of L-1 and D-II are given as examples of the reaction pathway).
  • N of the crude product the N- dimethylformamidine de (2 mL) solution of imidazole (138. Omg) was added, O e C in t one-heptyl dimethylsilyl click chloride de (TBDMS- C 1) (1 After adding 67. Omg), the mixture was stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with geethyl ether. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The residue was purified by silica gel column chromatography to obtain 302 mg of [(2S, 1'S, 2'S) 13] from the eluted portion.
  • the ether extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography to obtain 92 mg of [(2R, 1 ′S, 2 ′S) —4] from a portion eluted with ethyl hexanoacetate (15Z1, volume ratio). .
  • reaction solution was concentrated, and purified by reverse phase column chromatography (ODS column) HPLC using (H 2 0), [( 2 R, 1 'S, 2' S) -9] ( compound of the present invention 18.7 mg of D— ⁇ : (2R, 1 ′S, 2 ′S) -2- (2′—carboxy-3 ′, 3′difluoro) cyclopropylglycine) was obtained.
  • the obtained residue was purified by silica gel column chromatography to obtain 3.5 g of [(2R, ⁇ S, 2'S) —11] from a portion eluted with hexane ethyl acetate (30Z1, volume ratio). .
  • the compound of the present invention B / I [(2S. ⁇ , 2'R) -10], that is, (2S, 1'R, 2'R) -2-(2 'one carboxy 1 3 ', 3' difluoro) Cyclopropylglycine [Hydrogen monomethylester hydrochloride was obtained.
  • the depolarization of a splenectomized neonatal rat specimen induced by the test drug was performed according to the method of Shinozaki et al. (Br. J. Pharmacol. 98, 1213-1224, 1899). That is, using a neonatal rat spinal cord extirpation specimen, extracellular recordings of depolarization from the anterior root of motor neurons were obtained under the flow of artificial cerebrospinal fluid containing 0.5 ⁇ M of tetrodotoxin, using a known mG 1 uR agonist. is CCG is - for (2 (carboxycyclobutyl Purobiru) glycine) and the compound of the present invention, was measured at concentrations 10- 3 ⁇ 10 ⁇ 7 ⁇ , determine the minimal effective concentration (MEC).
  • the activity is determined by the minimum effective concentration (MF! C) of each CCG corresponding to the optical configuration of each of the preferred compounds of the present invention (8 types: L :! to [V,])-1 to IV). (L-I to IV and D-I to IV all used hydrochloride). Table I shows the results. Table 1: Ratio of CCG activity intensity for corresponding optical configurations
  • the NMD A-like depolarization by the compound L-I of the present invention is performed by a known substance, DCG-IV
  • the monosynaptic reflex measurement in the splenectomized neonatal rat specimen was performed according to the method reported by Otsuka (Masunori Otsuka, Biological Sciences, Vol. 36, No. 4, pp. 325-327). That is, the spinal cord of a newborn Wistar rat was excised under ether anesthesia while surrounded by the spinal column, and immersed in artificial cerebrospinal fluid saturated with 95% oxygen and 5% carbon dioxide from L3 under a stereoscopic microscope. Transfer the excised spinal cord excision specimen with the anterior and posterior roots up to L5 to the ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ .
  • the mono-synaptic reflex was measured by adding various concentrations of the test drug to the port liquid, and its minimum effective concentration (MEC) was determined.
  • the minimum effective concentration of L-CCG-I a known mG 1 uR agonist, is 0.2 uM, and the cyclobutyractylpyrglycine derivative L-I of the present invention suppresses spinal cord monosynaptic reflex three-fold. It was confirmed that.
  • L-I also attenuated the spinal monosynaptic reflex, and this effect was suppressed by MCCG, an angios gonist of group III of mG1 uR.
  • this L-I has the function of the agonist of group I and group I of mG1 uR, and it can be said that the agonist action of group I is strong when compared at the minimum effective concentration.
  • L-I is insensitive to CNQX, a non-NMDA receptor antagonist, and is considered to be a group I agonist of mG1uR.
  • L-ffl loses the inhibitory effect of glutamate uptake on L-CCG- ⁇ 1 s transporter (Nihon Pharmaceutical Journal, 104, 177-187 (1994), Br. Pharmacol. 98, 1213-: 1224, 1989].
  • the cyclopropylglycine derivative of the present invention in particular, (2S, ⁇ S, 2'S) -12- (2, -carboxy-3 ', 3'-difluoro) cyclobutene building Glycine has excellent properties as a metabolic-regulated L-glutamate receptor agonist, and is derived from various neurodegenerative diseases such as Huntington's disease, epilepsy, Parkinson's disease, and ischemic neuronal death. It is expected to be used as a sedative, analgesic, anesthetic enhancer or anticonvulsant in the treatment of various cerebral central dysfunctions.
  • cyclobutyrvir glycine derivative of the present invention provides a clue to the development of glutamate receptor antagonists and the like, and is expected to be useful as various reagents and pharmaceuticals.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne de nouveaux dérivés de cyclopropylglycine représentés par la formule générale (I), ainsi que des intermédiaires permettant leur synthèse. Dans cette formule, R1 et R2 représentent chacun indépendamment hydroxy ou bien alcoxy C¿1?-C6; R?3 et R4¿ représentent chacun indépendamment hydrogène ou bien alkyle C¿1?-C6, et X?1 et X2¿ représentent chacun indépendamment halogéno. Ces dérivés servent d'agoniste du récepteur du L-glutamate du type à régulation métabolique, lequel présente une forte sélectivité et d'excellentes caractéristiques par rapport aux agonistes connus.
PCT/JP1996/003849 1996-06-28 1996-12-27 Derives de cyclopropylglycine et agoniste du recepteur du l-glutamate du type a regulation metabolique Ceased WO1998000391A1 (fr)

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Application Number Priority Date Filing Date Title
EP96943327A EP0913389A4 (fr) 1996-06-28 1996-12-27 Derives de cyclopropylglycine et agoniste du recepteur du l-glutamate du type a regulation metabolique

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JP18852096 1996-06-28
JP8/188520 1996-06-28

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172058B1 (en) 1997-04-08 2001-01-09 Lilly, Sa Compounds with pharmaceutical properties
US6478423B1 (en) 1999-10-12 2002-11-12 Johnson & Johnson Vison Care, Inc. Contact lens coating selection and manufacturing process
US6498180B1 (en) 1999-06-03 2002-12-24 Eli Lilly And Company Excitatory amino acid receptor modulators
US6504052B1 (en) 1999-06-03 2003-01-07 Eli Lilly And Company Excitatory amino acid receptor modulators
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
AU2012201015B2 (en) * 2000-08-31 2013-10-17 Janssen Pharmaceutica Nv Peptidomimetic protease inhibitors
HRP20030139B1 (hr) * 2000-08-31 2015-08-28 Janssen Pharmaceutica Nv Peptidomimetiäśki inhibitori proteaza

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020188022A1 (en) * 2000-10-30 2002-12-12 Annovis. Inc. Methods for modulation, stimulation, and inhibition of glutamate reuptake

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0193563A (ja) * 1987-06-30 1989-04-12 Suntory Ltd （２Ｓ，３Ｒ，４Ｓ）―α―（カルボキシシクロプロピル）グリシン及びその製造法
JPH0624970A (ja) * 1992-10-19 1994-02-01 Suntory Ltd 代謝調節型ｌ−グルタミン酸受容体アゴニスト

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0193563A (ja) * 1987-06-30 1989-04-12 Suntory Ltd （２Ｓ，３Ｒ，４Ｓ）―α―（カルボキシシクロプロピル）グリシン及びその製造法
JPH0624970A (ja) * 1992-10-19 1994-02-01 Suntory Ltd 代謝調節型ｌ−グルタミン酸受容体アゴニスト

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP0913389A4 *
TETRAHEDRON, 52(1), (1996), SHIBUYA, AKIRA; KURISHITA, MASAHITO; AGO, CHIZURU; TAGUCHI, TAKEO, "A Highly Diastereoselective Synthesis of Trans-3,4-(Difluoromethano) Glutamic Acid", p. 271-278. *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6172058B1 (en) 1997-04-08 2001-01-09 Lilly, Sa Compounds with pharmaceutical properties
US6498180B1 (en) 1999-06-03 2002-12-24 Eli Lilly And Company Excitatory amino acid receptor modulators
US6504052B1 (en) 1999-06-03 2003-01-07 Eli Lilly And Company Excitatory amino acid receptor modulators
US6478423B1 (en) 1999-10-12 2002-11-12 Johnson & Johnson Vison Care, Inc. Contact lens coating selection and manufacturing process
HRP20030139B1 (hr) * 2000-08-31 2015-08-28 Janssen Pharmaceutica Nv Peptidomimetiäśki inhibitori proteaza
HRP20030139B8 (hr) * 2000-08-31 2015-11-06 Janssen Pharmaceutica Nv Peptidomimetiäśki inhibitori proteaza
AU2012201015B2 (en) * 2000-08-31 2013-10-17 Janssen Pharmaceutica Nv Peptidomimetic protease inhibitors
EP2258357A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
EP2258358A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2258359A2 (fr) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
EP2275095A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2275096A2 (fr) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese par modulation des recepteurs muscariniques
EP2377530A2 (fr) 2005-10-21 2011-10-19 Braincells, Inc. Modulation de neurogénèse par inhibition PDE
EP2314289A1 (fr) 2005-10-31 2011-04-27 Braincells, Inc. Modulation de la neurogenese dont la médiation est assurée par récepteur gaba
EP2377531A2 (fr) 2006-05-09 2011-10-19 Braincells, Inc. Neurogénèse par modulation de l'angiotensine
EP2382975A2 (fr) 2006-05-09 2011-11-02 Braincells, Inc. Neurogénèse par modulation d'angiotensine
WO2010099217A1 (fr) 2009-02-25 2010-09-02 Braincells, Inc. Modulation de neurogenèse à l'aide de combinaisons de d-cyclosérine
WO2011063115A1 (fr) 2009-11-19 2011-05-26 Braincells Inc. Combinaison d'un agent nootropique avec un ou plusieurs agents neurogènes ou à effet neurogène par synergie pour stimuler ou intensifier la neurogenèse
WO2011091033A1 (fr) 2010-01-20 2011-07-28 Braincells, Inc. Modulation de la neurogenèse par des agents ppar

Also Published As

Publication number Publication date
EP0913389A1 (fr) 1999-05-06
EP0913389A4 (fr) 2000-02-02

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